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§13—7有机合成路线一、碳胳的生成1．增长碳链⑴任意增长⑵增加一个C炔烃RCCHRCCNaNaR'XRCCR'芳烃（付-克反应）ArHRXRCOXAlCl3ArCORAr-RAlCl3卤代烃2RXRXR-RRLiLiR2CuLiR-R'Na(武尔慈反应)CuIR'X羟醛缩合2RCH2CHORCH2CH-CHCHOOH-OHRRCHOR2CORCOLH2OR'MgXH2OR'MgXH2OR'MgXRCHOHR2C-OHR-C-OHR'R'R'R'格氏试剂和羰基的反应RCH=OR'CH=P(C6H5)3RCH=CHR'+H2ORXCN-[H]RCOOHRCH2NH2MgCO2HCNRCHO(CH3)RXH2ORCOOHRCHOHCNWitting反应R2C=OR'CH=P(C6H5)3R2C=CHR'+⑶增加二个C乙酰乙酸乙酯和丙二酸二乙酯2．缩短碳链G为吸电子基3．形成叁键4．形成双键RMgXCH2H2CO+H2ORCH2CH2OHRCH=CHR'[O]RCOOHR'COOHRCH=CR'R''O3RCHOR'R''C=O+Zn/H2O+Ar-RArCOOH[O]RCONH2霍夫曼降解反应Br2+NaOHRNH2RCHCOOHH2SO4RCHOOH+CO2△RCHCOOHG+RCH2GRCOCH3NaOX甲基酮X2+NaOHRCOONaCHX3+RCH-CH-R'-HXOH-R-CRCX2-CX2-R'XX-X2CR'ZnR-CR-CCR'R-CR-C=CHR'R-CH-CH2R'OHRCH-CH2-R'XOH-/醇H+R-C=CHR'+RCCR`H2喹啉Pd/BaSO4RCCR`HH+RCCR`H2Na液氨RCCR`HH二、形成碳环的反应1．小环的合成⑴分子内的烷基化X=卤代物或磺酸盐离子。Y=-CN、-COR、-COOR⑵卡宾对烯的加成⑶[2+2]环加成2．普通环（五、六元环）⑴付-克酰基化⑵狄克曼反应（分子内酯缩合）⑶分子内羟酸缩合。XYHOH-XY-分子内亲核取代YX-+X-+XYHOH-XY-分子内亲核取代YCH2R-CH=CHR+CHHCCH2RR+hvCH2CH2CH2COOHγ-内酯OHH2CCH2OCH2COCH2CH2CH2COXAlCl3OZn/HgHCl⑷Diels-Alder反应（双烯合成）⑸麦克尔反应（Michael反应）3．乙酰乙酸乙酯和丙二酸二乙酯可合成任意环4．大环—联姻缩合（二酯在金属Na条件下进行分子内缩合）三、转换官能团的反应1．官能团的引入⑴碳卤键的形成+COOCH3(CH2)8COOCH3NaHAc二甲苯(H2C)6CHCOOHRXX2HXRH+hv+RC=CR'RCH=CXR'RCCR'X2HXXXRCH2CH=CH2HXHBrH2O2NBSHOXRCH2CHXCH3马氏规则RCH2CH2CH2Br反马氏规则RCHBrCH=CH2α-取代RCH2CHXCHXRCH2CHCH2或Br2/高温X2OHXCH2HCCOCH3CH3O+CH3ONaMicheal反应CH3OCH3OOH-△羟醛缩合CH3O⑵碳氧键的形成a．醇C—OHR-OHPX3X2RXRXFeBr3(Cl,Br)XX2HNO3H2SO4[H]NaNO2H+HBF4HCl-CuClHBr-CuBrKIN2+FClBrIRCH=CH2H2O2OH-RCH2CH2OHROHRXH2ORMgXHCHOR2CORCH2OHRR'CHOHR3COH伯醇仲醇叔醇OH-H2OH2OH2OH2OH2OH2OOH2CCH2RCH2CH2OHR'CHORCOClRCOOR`B2H6RCHOR2COR2CHOH[H]RCOOR'LiAlH4[H]RCH2OHRCH2OH仲醇伯醇KMnO4HO-OHOHOsO4OHOHOHHOC6H5COOOH+b．Ar—OH异丙苯氧化法；氯苯水解法；磺化碱熔法；重氮盐水解法。c．醚C—O—Cd．醛、酮·积二卤代烃水解·烃的氧化·醇的脱H或氧化·羧酸的还原·芳烃的酰基化·羰基化·α，β—羟酸的氧化脱羧·乙酰乙酸乙酯合成酮类·α—羟酸的水解e．羧酸·腈的水解OHN2+H2OH+,△RXR'ONaROR'ROR-H2OCH2N2RCOCH3+2ROHROH+RCHCOOHRCCOOHRCHOCO2[O]RCCH3OHOO△RCHCH2COOHRCCH2COOHOHO[O]+CO2△H2OHCOOHCORCHCOOHOHH2SO4浓△RCHO++稀H2SO4△RCHO+R2CCOOHOHH2SO4浓△稀H2SO4△R2COH2OCO++R2COHCOOH+·格氏试剂与CO2作用，水解·醛、醇、取代芳烃、烯烃的氧化·羧酸衍生物的水解·甲基酮的氧化（卤仿反应）·丙二酸二乙酯、乙酰乙酸乙酯合成羧酸2．官能团的除去⑴取代芳烃（—SO3H，—N2+）⑵羰基（还原亚甲基）A.Kishner—Wolff—黄呜龙反应:NH2NH2,EtOH/KOH,180℃B.Clemmensen还原法:Zn—Hg，浓HCl⑶羟基（脱水、加氢）3．官能团的转换四、有机合成路线的设计基本要求：·原料易得·反应步骤少·实验操作方便安全·反应产率高，付反应少，后处理简单（易纯化）1．增长碳链例2：由三个碳原子以下化合物合成2,2-二甲基戊酸。-C6H5CH=CH2Br2HBr2NaNH2NH3CH3CH2CH2BrTMH2Pt例1C6H5CH=CH2C6H5CH2CH2CH2CH2CH3HBrOMgBrH2OOHMg乙醚H2OCO2COOH例3由三个碳原子以下的化合物合成CH2=CH-CH2-CH-C-CH2-CH3OCH3CH3CH2COOHCH3CH2OHH+CH3ONaCH3CH2COOC2H5CH3ONaCH2=CHCH2ClCH3-C-COOC2H5COCH2CH3CH2-CH=CH2H+-CO2△CH3-CH-COOC2H5COCH2CH3酯缩合CH3-C-HCOCH2CH3CH2-CH=CH2方法一：方法二：2．碳环的合成3．保护基的作用例4合成C6H5C-CH2-CHCH2COOHOC6H5C6H5CHOC6H5CCH3O+OH-C6H5C-CH=CHOC6H5CH2(COOC2H5)2EtONaHBrC6H5C-CH2CHBrOC6H5C6H5C-CH2CHOC6H5CH(COOC2H5)2H+-CO2△C6H5C-CH2-CHCH2COOHOC6H5例5由甲苯合成CH3OOO+无水AlCl3CH3HOOCOZn/HgHClCH3HOOC多聚磷酸CH3O(CH3)2CHMgBrH2O△脱水S脱氢C6H5CHOC6H5CCH3O+OH-CH2(COOC2H5)2EtONaH+-CO2△C6H5C-CH2-CHCH2COOHOC6H5CHHCCOC6H5C6H5CHH2CCOC6H5C6H5CH(COOC2H5)2⑴要求：·易于与被保护基反应。·保护基团相对稳定.·又容易除去。⑵常见的保护方法：·烯·醛、酮通过缩醛（或酮）来保护。·醇羟基变成醚（或酯）来保护。·酚羟基变成苯甲醚来保护。例6：CCBr2ZnArOHNaOHCH3IHIArOCH3ArOHCH3I+RCHOCH3OH+干HClH+RCHOCH3OCH3RCHOR2COCH2OHCH2OH+干HClR2CCH2CH2OOH+R2CORCH2OHPh3CClRCH2OCPh3HAcH2ORCH2OHRCH2OHR`COOH+H+R`COOCH2RH2OH+RCH2OHCH3CCH2CCH3CH3OCH2BrCH3CCH2CCH3CH3OCH2COOH乙二醇H+CH3CCH2CCH3CH3CH2BrCH2H2COOMg干醚CO2H+H2OTM例7：由香茅醛合成HOOC-CH2CH2CH(CH3)CH2CHO。例8：由HOCH2C≡CH合成HOCH2C≡CCOOCH3。4．逆合成法OHCH3CH3abCCH3O+CH3MgICHCH3HObOH3CCHBrMgBrCH3-C-CH3OMgBrBr++a例9：BrMg(C2H5)2OCH3COCH3H3O+OHCH3CH3HBrOCH3OHHCl干OCH3OCH3KMnO4H+HOOCOHOCH2≡CHOH+OOCH2C≡CHC2H5MgBrCO2CH3OHH+HOCH2C≡CCOOCH3例10：试设计2-苯基-2-丁烯的合成路线CCH3H3CHCCCH3HOH3CH2CacbCMgBrCH3OCH3CH2MgBrCH3CH2CCH3CH3MgBr+CCH2CH3O+O+abcH2OCH3CH2CCH3OMgBrH3O+CCH3H3CHC△COOHBrOHOCO2H3O+PBr3NaBH4Mg/Et2OCH3COClAlCl3Zn-HgHClOAlCl3+ClO例11：①②例12：OHOHOOCHOOCO+OOO[小结]：·官能团处先拆·链分支处先拆·碳—杂原子键处先拆·由两个官能团形成的官能团处先拆分为原官能团5．导向基的引入这是合成路线设计中一个十分重要的技巧，一般是—NH2，—SO3H，借来实现特定的合成目的，任务完成后又还其本来面目，将借来的基团去掉。OHOHOOCHOOCO+OOOAlCl3Zn-HgSOCl2MgBrH2OAlCl3H3O+△例13：OOHOOHOHOOHCHOOHCHO+HCHOOOHOOHCOHOOHCHOOHCHO+HCHOHCN稀OH-H3O+H3O+△CH3H3CCHHCCH3CH3CH3例14：试设计2-甲基-3-(2,4-二甲苯基)丁烷例15：邻氯甲苯例16：由氯苯合成2,6-二硝基苯胺。CH3磺化Cl2FeH3O+CH3ClCH3H3CCHCHCH3H3CCH3CH3H3CCCHCH3H3CCH3OHCH3H3CCCH3OCHCH3H3C+MgBrCH3H3C+CH3COClCH3H3CCCCH3CH3CH3CH3H3CCCHCH3H3CCH3OHCH3H3CCCH3OCHMgBrH3CH3CCH3H3CCH3COClAlCl3H2O①②H+H2OCH3H3CHCCHCH3H3CCH3H2Pd/C-CH3CH3ClCH3ClCl2Fe+b.P.162℃b.P.159℃二者沸点接近,分离困难Cl磺化ClSO3H(分离邻位异构体)硝化H2O△ClNO2O2NNH3NH2NO2O2N6．合成路线的选择例17：由苯合成苯乙酮。显然方法二步骤小，而且产量高。例18：从卤代烃合成羧酸可通过下列两种途径：这两种方法都可以用。但如果合成2,2-二甲基丁酸,最好用方法一。方法二不能用，因为在亲核试剂作用下，叔卤代烷容易发生消除反应。总之，对于一个化合物可以有几种合成路线，何种方法优越，既要考虑原料的来源，又要考虑合成路线步骤的多少，以及每步合成的得率，实验条件的难易。所以一个合理的路线需要衡量各方面因素，才能最后确定。方法一：CH2=CH2AlCl3CH2CH3Cl2光C-CH3ClCl水解C-CH3O方法二：C-CH3OCH3COCClAlCl3方法一：RXCO2H2OMg干醚RCOOHRXH2ORCOOH方法二：CN-CO2Mg干醚CH3CH2-C-BrCH3CH3水解CH3CH2-C-COOHCH3CH3